Extensive variability in severity and survival is a common feature of acute respiratory distress syndrome (ARDS), and identification of mechanisms that regulate this variability may lead to more personalized treatment. Age, race, cigarette smoking, and alcoholism impair the immune system, and are linked to increased prevalence or worse ARDS outcomes (Iribarren C, et al. (2000) Cigarette smoking, alcohol consumption, and risk of ARDS: a 15-year cohort study in a managed care setting. Chest 117: 163-168.; Calfee C S, et al. (2011) Active and passive cigarette smoking and acute lung injury after severe blunt trauma. Am J Respir Crit Care Med 183: 1660-1665.; Hudson L, et al. (1995) Clinical risk for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 151: 293-301.; Moss M, et al. (1996) The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. Jama 275: 50-54.; Milberg J A, et al. (1995) Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983-1993. Jama 273: 306-309.; Ely E W, et al. (2002) Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 136: 25-36.; Kangelaris K N, et al. (2012) The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury. Chest 141: 1160-1169.; Moss M, Mannino D M (2002) Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiple-cause mortality data (1979-1996). Crit Care Med 30: 1679-1685.; Rubenfeld G D, et al. (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685-1693.). Specific forms of inflammatory dysregulation are also linked to worse outcomes from sepsis or ARDS, including coding variations in over 25 genes (Matthay M A, Ware L B, Zimmerman G A (2012) The acute respiratory distress syndrome. J Clin Invest 122: 2731-2740.; Gao L, Barnes K C (2009) Recent advances in genetic predisposition to clinical acute lung injury. Am J Physiol Lung Cell Mol Physiol 296: L713-725.; Arcaroli J, et al. (2005) Genetic Polymorphisms And Sepsis. Shock 24: 300-312.). ARDS is most commonly precipitated by pneumonia or sepsis (Rubenfeld G D, et al. (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685-1693.; Ware L B, Matthay M A (2000) The acute respiratory distress syndrome. N Engl J Med 342: 1334-1349.), resulting in massive neutrophil accumulation within the pulmonary vasculature (Abraham E (2003) Neutrophils and acute lung injury. Crit Care Med 31: S195-199.). Both over-exuberant or diminished innate immune response to bacterial products can worsen clinical outcomes, as the protective benefit of pathogen killing is balanced against the considerable injurious capacity of neutrophils (Lamb N J, et al. (1999) Oxidative damage to proteins of BAL fluid in patients with ARDS: Evidence for neutrophil-mediated hydroxylation, nitration, and chlorination. Critical Care Medicine 27: 1738-1744.; Borregaard N, Cowland J B (1997) Granules of the Human Neutrophilic Polymorphonuclear Leukocyte. Blood 89: 3503-3521.). Various stimuli may evoke complex “adaptive” responses to pathogens by neutrophils, by either decreasing (tolerance) or increasing (priming) activation (Buckley J M, Wang J H, Redmond H P (2006) Cellular reprogramming by gram-positive bacterial components: a review. J Leukoc Biol 80: 731-741.; Fan H, Cook J A (2004) Molecular mechanisms of endotoxin tolerance. J Endotoxin Res 10: 71-84.). Neutrophil function appears dysregulated in ARDS (Lee K S, et al. (2008) Evaluation of bronchoalveolar lavage fluid from ARDS patients with regard to apoptosis. Respir Med 102: 464-469.; Aggarwal A, (2000) G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J 15: 895-901.; Goodman R B, et al. (1996) Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 154: 602-611.; Lesur O, et al. (2000) Interleukin-2 involvement in early acute respiratory distress syndrome: relationship with polymorphonuclear neutrophil apoptosis and patient survival. Crit Care Med 28: 3814-3822.; Mascellino M T, et al. (2001) Reduced bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa of blood neutrophils from patients with early adult respiratory distress syndrome. J Med Microbiol 50: 49-54.; Martin T R, et al. (1991) The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections. Am Rev Respir Dis 144: 254-262.; Rivkind A I S J, et al. (1991) Neutrophil oxidative burst activation and the pattern of respiratory physiologic abnormalities in the fulminant post-traumatic adult respiratory distress syndrome. Circ Shock 33: 48-62.; Fialkow L, et al. (2006) Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome. Crit Care 10: R155.), and the potential exists that a beneficial adaptation to one microbe may place the host at a disadvantage against other infectious agents or inflammatory insults.
Viral infections can modify the immune response to subsequent bacterial infections (McNamee L A, Harmsen A G (2006) Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary Streptococcus pneumoniae infection. Infect Immun 74: 6707-6721.; Brundage J F (2006) Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. Lancet Infect Dis 6: 303-312.; Brundage J F, Shanks G D (2008) Deaths from bacterial pneumonia during 1918-19 influenza pandemic. Emerg Infect Dis 14: 1193-1199.; Metzger D W, Sun K (2013) Immune dysfunction and bacterial coinfections following influenza. J Immunol 191: 2047-2052.; Sun K, Metzger D W (2008) Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 14: 558-564.; Rothberg M B, et al. (2008) Complications of viral influenza. Am J Med 121: 258-264.; Sellers T F, et al. (1961) The influence of influenza virus infection on exogenous staphylococcal and endogenous murine bacterial infection of the bronchopulmonary tissues of mice. J Exp Med 114: 237-256.; McCullers J A (2006) Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 19: 571-582.), and thus could predispose to ARDS. A principal immune response to viral infections is production of the Type I interferons (IFNα and IFNβ), which are evoked by a broad range of viral factors, and in turn upregulate expression of interferon-stimulated genes (ISG) (Stetson D B, Medzhitov R (2006) Type 1 interferons in host defense. Immunity 25: 373-381.; Roers A, et al. (1994) MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon. J Infect Dis 169: 807-813.; Halminen M, et al. (1997) Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children. Pediatr Res 41: 647-650.; Ramilo O, et al. (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109: 2066-2077.; Zaas A K, et al. (2009) Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 6: 207-217.). Hundreds of diverse ISG have been identified, with gene products which may act to reduce viral replication and release (Metz P, Reuter A, Bender S, Bartenschlager R (2013) Interferon-stimulated genes and their role in controlling hepatitis C virus. J Hepatol 59: 1331-1341.), or alternatively function as inflammatory cytokine (Stetson D B, Medzhitov R (2006) Type 1 interferons in host defense. Immunity 25: 373-381.; Schoggins J W, et al. (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472: 481-485.; Pichlmair A, Reis e Sousa C (2007) Innate recognition of viruses. Immunity 27: 370-383.). However, ISG upregulation is neither sensitive nor specific for viral infection. Not all viral infections trigger the response, and certain intracellular bacteria or systemic autoimmune disorders have also been associated with IFNα/β release and ISG upregulation (Stetson D B, Medzhitov R (2006) Type 1 interferons in host defense. Immunity 25: 373-381.; Parker D, et al. (2014) Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog 10: e1003951.). In animal models and human neutrophils, elevated IFNα/β release and/or ISG expression has been reported to be associated with impaired response to specific bacteria (Parker D, et al. (2014) Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog 10: e1003951.; Mancuso G, et al. (2007) Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. J Immunol 178: 3126-3133.; Carrero J A, Calderon B, Unanue E R (2004) Type I interferon sensitizes lymphocytes to apoptosis and reduces resistance to Listeria infection. J Exp Med 200: 535-540.; O'Connell R M, et al. (2004) Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 200: 437-445.; Kelly-Scumpia K M, et al. (2010) Type I interferon signaling in hematopoietic cells is required for survival in mouse polymicrobial sepsis by regulating CXCL10. J Exp Med 207: 319-326.; Malcolm K C, et al. (2011) Bacteria-Specific Neutrophil Dysfunction Associated with Interferon-Stimulated Gene Expression in the Acute Respiratory Distress Syndrome. PLoS 6: e21958.). Conversely, severe bacterial-induced inflammation can suppress Type I IFN-regulated pathways, and certain viruses have acquired virulence factors which inhibit ISG (Brukman A, Enquist L W (2006) Suppression of the interferon-mediated innate immune response by pseudorabies virus. J Virol 80: 6345-6356.; Eidson K M, et al. (2002) Expression of herpes simplex virus ICP0 inhibits the induction of interferon-stimulated genes by viral infection. J Virol 76: 2180-2191.; Kotla S, et al. (2008) Attenuation of the type I interferon response in cells infected with human rhinovirus. Virology 374: 399-410.; Kumthip K, et al. (2012) Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling. J Virol 86: 8581-8591.; Ivashkiv L B, Donlin L T (2014) Regulation of type I interferon responses. Nat Rev Immunol 14: 36-49.; Bode J G, Brenndorfer E D, Haussinger D (2007) Subversion of innate host antiviral strategies by the hepatitis C virus. Arch Biochem Biophys 462: 254-265.). Together, these findings suggest that both elevated and suppressed ISG expression is associated with more severe outcomes in ARDS. However, it is noted that variability in the severity and duration of Acute Respiratory Distress Syndrome (ARDS) is incompletely understood, and has not been associated with Interferon-stimulated genes (ISG) expression.